Macrophages: key players in erythrocyte turnover

ABSTRACT The development of red blood cells (RBCs), or erythropoiesis, occurs in specialized niches in the bone marrow, called erythroblastic islands, composed of a central macrophage surrounded by erythroblasts at different stages of differentiation. Upon anemia or hypoxemia, erythropoiesis extends to extramedullary sites, mainly spleen and liver, a process known as stress erythropoiesis, leading to the expansion of erythroid progenitors, iron recruitment and increased production of reticulocytes and mature RBCs. Macrophages are key cells in both homeostatic and stress erythropoiesis, providing conditions for erythroid cells to survive, proliferate and differentiate. During RBCs aging and injury, macrophages play a fundamental role again, performing the clearance of these cells and recycling iron for new erythroblasts in development. Thus, macrophages are crucial components of the RBCs turnover and in this review, we aimed to cover the main known mechanisms involved in the process of birth and death of RBCs, highlighting the importance of macrophage functions in the whole RBC lifecycle.

Macrophages: key players in erythrocyte turnover.

The development of red blood cells (RBCs), or erythropoiesis, occurs in specialized niches in the bone marrow, called erythroblastic islands, composed of a central macrophage surrounded by erythroblasts at different stages of differentiation. Upon anemia or hypoxemia, erythropoiesis extends to extramedullary sites, mainly spleen and liver, a process known as stress erythropoiesis, leading to the expansion of erythroid progenitors, iron recruitment and increased production of reticulocytes and mature RBCs. Macrophages are key cells in both homeostatic and stress erythropoiesis, providing conditions for erythroid cells to survive, proliferate and differentiate. During RBCs aging and injury, macrophages play a fundamental role again, performing the clearance of these cells and recycling iron for new erythroblasts in development. Thus, macrophages are crucial components of the RBCs turnover and in this review, we aimed to cover the main known mechanisms involved in the process of birth and death of RBCs, highlighting the importance of macrophage functions in the whole RBC lifecycle.

Inflammatory Dendritic Cells Contribute to Regulate the Immune Response in Sickle Cell Disease.

Sickle cell disease (SCD), one of the most common hemoglobinopathies worldwide, is characterized by a chronic inflammatory component, with systemic release of inflammatory cytokines, due to hemolysis and vaso-occlusive processes. Patients with SCD demonstrate dysfunctional T and B lymphocyte responses, and they are more susceptible to infection. Although dendritic cells (DCs) are the main component responsible for activating and polarizing lymphocytic function, and are able to produce pro-inflammatory cytokines found in the serum of patients with SCD, minimal studies have thus far been devoted to these cells. In the present study, we identified the subpopulations of circulating DCs in patients with SCD, and found that the bloodstream of the patients showed higher numbers and percentages of DCs than that of healthy individuals. Among all the main DCs subsets, inflammatory DCs (CD14+ DCs) were responsible for this rise and correlated with higher reticulocyte count. The patients had more activated monocyte-derived DCs (mo-DCs), which produced MCP-1, IL-6, and IL-8 in culture. We found that a CD14+ mo-DC subset present in culture from some of the patients was the more activated subset and was mainly responsible for cytokine production, and this subset was also responsible for IL-17 production in co-culture with T lymphocytes. Finally, we suggest an involvement of heme oxygenase in the upregulation of CD14 in mo-DCs from the patients, indicating a potential mechanism for inducing inflammatory DC differentiation from circulating monocytes in the patients, which correlated with inflammatory cytokine production, T lymphocyte response skewing, and reticulocyte count.

Clinical relevance of heterozygosis for aceruloplasminemia.

Aceruloplasminemia is a rare form of brain iron overload of autosomal recessive inheritance that results from mutations in the CP gene, encoding the iron oxidase ceruloplasmin. Homozygous aceruloplasminemia causes progressive neurodegenerative disease, anemia, and diabetes, and is usually diagnosed late in life upon investigation of anemia, high ferritin, or movement disorders, but its heterozygous state is less characterized and believed to be silent. Here we report two heterozygotes for new mutations causing aceruloplasminemia from whom peripheral blood samples were collected for complete blood counts, iron studies, and genotyping by automated sequencing. We then performed a systematic review of preview reports of heterozygotes with data on genotype and clinical findings. Heterozygosity for aceruloplasminemia invariably causes reduced ceruloplasmin levels, and similarly to previews reports in the literature, our cases did not present with anemia. Mild hyperferritinemia was found only in two reports. Nevertheless, 5 out of 11 variants have been associated with significant neurological symptoms despite the presence of one wild-type alelle. This review contributes to better genetic counseling of heterozygotes for CP gene variants and supports that measuring ceruloplasmin levels may be useful when investigating patients with movement disorders or rare cases of unexplained high ferritin.